Sac2/INPP5F is an inositol 4-phosphatase that functions in the endocytic pathway

J Cell Biol. 2015 Apr 13;209(1):85-95. doi: 10.1083/jcb.201409064.


The recruitment of inositol phosphatases to endocytic membranes mediates dephosphorylation of PI(4,5)P2, a phosphoinositide concentrated in the plasma membrane, and prevents its accumulation on endosomes. The importance of the conversion of PI(4,5)P2 to PtdIns during endocytosis is demonstrated by the presence of both a 5-phosphatase and a 4-phosphatase (Sac domain) module in the synaptojanins, endocytic PI(4,5)P2 phosphatases conserved from yeast to humans and the only PI(4,5)P2 phosphatases in yeast. OCRL, another 5-phosphatase that couples endocytosis to PI(4,5)P2 dephosphorylation, lacks a Sac domain. Here we show that Sac2/INPP5F is a PI4P phosphatase that colocalizes with OCRL on endocytic membranes, including vesicles formed by clathrin-mediated endocytosis, macropinosomes, and Rab5 endosomes. An OCRL-Sac2/INPP5F interaction could be demonstrated by coimmunoprecipitation and was potentiated by Rab5, whose activity is required to recruit Sac2/INPP5F to endosomes. Sac2/INPP5F and OCRL may cooperate in the sequential dephosphorylation of PI(4,5)P2 at the 5 and 4 position of inositol in a partnership that mimics that of the two phosphatase modules of synaptojanin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Endocytosis*
  • Endosomes / enzymology*
  • HEK293 Cells
  • Humans
  • Inositol Polyphosphate 5-Phosphatases
  • Mice, Knockout
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphoric Monoester Hydrolases / physiology*
  • Protein Transport
  • rab5 GTP-Binding Proteins / metabolism


  • Phosphoric Monoester Hydrolases
  • Ocrl protein, mouse
  • INPP5F protein, human
  • Inositol Polyphosphate 5-Phosphatases
  • rab5 GTP-Binding Proteins